The use of dietary supplements containing botanical products is rapidly expanding in the United States. In the mass market alone, over $650 million is spent yearly on botanical supplements. The public is using these products for a wide range of health-related problems, including chronic inflammatory diseases such as chronic obstructive pulmonary disease, asthma and rheumatoid arthritis. Yet, firm scientific information about botanicals and their active ingredients is not currently available. Used for centuries in Ayurvedic medicine, a number of these botanical supplements have been purported to have anti-inflammatory actions.
Turmeric, the powdered rhizome of the herb Curcuma longa L. (Zingiberaceae), has been used extensively in curries and mustards as a coloring and flavoring agent. Powdered turmeric, or its extract, is found in numerous commercially available botanical supplements. In Ayurvedic medicine turmeric has traditionally been used to treat inflammation, skin wounds and tumors. (Ammon and Wahl, 1991, Planta Med., 57:1–7). Turmeric extracts have been reported to have antimicrobial, anti-inflammatory, antioxidant and anticancer effects. In preclinical animal studies turmeric has shown anti-inflammatory, cancer chemopreventive and anti-neoplastic properties (Kelloff et al., 1996, J. Cell. Biochem. Supplement 26:54–71). The best characterized of the compounds found in turmeric is curcumin, which has been shown to reduce inflammation.
Inflammation is associated with a large collection of mediators that initiate the inflammatory response, recruit and activate other cells to the site of inflammation and subsequently resolve the inflammation (Gallin and Snyderman, 1999, Overview in INFLAMMATION: BASIC PRINCIPLES AND CLINICAL CORRELATES, 3 d ed., Lippincott Williams & Wilkins, Philadelphia, pp. 1–3). Cytokines are regulatory polypeptides that are produced by virtually all cells (For review, see THE CYTOKINE HANDBOOK, 1998, ed by A. Thomson, 3d edition, Academic Press, New York City). In general, cytokines are not constitutively produced. However, in the presence of appropriate stimuli (for example, lipopolysaccharide (LPS) from gram negative bacteria), increased gene expression and production of cytokines occurs, leading to the initiation of an inflammatory response. Two major cytokines involved in the initiation of inflammation are tumor necrosis factor α (TNF-α) and interleukin 1 (IL-1). These proteins have multiple sites of action. Responses include induction of other cytokines, activation of arachidonic acid metabolism, priming of polymorphonuclear leukocytes (PMN), and up-regulation of adhesion molecules. Regulation of gene expression for these cytokines is in part controlled by activation of transcription factors such as nuclear factor of K light chain B (NF-κB) and activating protein 1 (AP-1).
In addition to cytokines, metabolites of arachidonic acid also participate in the inflammatory process. Products produced by the metabolism include both cyclooxygenase products (prostaglandins, thromboxanes) and lipooxygenase products (leukotrienes). Products such as leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) that are representative of these two pathways can initiate PMN recruitment and changes in vascular tone and blood flow. Increased production of prostaglandins during an inflammatory response is achieved by induction of cyclooxygenase 2 (COX-2). COX-2 expression is mediated by NF-κB activation (Plummer et al., 1999, Oncogene, 18:6013–6020).
Current treatment of inflammation includes aspirin, nonsteriodal anti-inflammatories and dexamethasone. Sites of action of these compounds range from inhibition of enzymes responsible for production of arachidonic acid metabolites to inhibition of cytokine expression.
Evaluation of the active ingredients in turmeric has focused primarily on curcumin, a polyphenylic responsible for the yellow color of turmeric. In vitro studies have demonstrated that curcumin will inhibit production of inflammatory mediators, such as TNF-α and IL-1 (Chan 1995, Biochem. Pharmacol. 49:1441–1556; Chan et al., 1998, Oncogene 17:173–178; Abe et al., 1999, Pharmacol. Res. 39:41–47). In addition, curcumin has been reported to also inhibit superoxide and PGE2 production and to inhibit expression of inducible nitric oxide synthase (iNOS) and COX-2 (Ruby et al., 1995, Cancer Lett. 94:79–83; Joe and Lokesh, 1997, Lipids 32:1173–1180; Chan et al., 1998; Hong et al., 2002, Ethnopharmacol. 83:153–159; and Hong et al., Planta Med. 68:545–547). For curcumin, data indicate that a major site of action is inhibition of transcription factor activation (Chan et al., 1998; Plummer et al., 1999, Oncogene 18:6013–6020: Jobin et al., 1999, J. Immunol. 163:3473–3483; Zhang et al., 1999, Carcinogenesis 20:445–451), including NF-κB and AP-1. Additionally, Chen and Tan (1998, Oncogene 17:173–178) have also shown that curcumin can inhibit kinase activity in the c-Jun N-terminal kinase pathway. This pathway is also responsible for activation of NF-κB and AP-1 transcription factors.
While the activity and sites of action of curcumin have been studied, the potential anti-inflammatory activity of other compounds in turmeric has not been systematically examined. Other potential anti-inflammatory compounds may be present in C. longa extracts. For example, sesquiterpenoids from C. xanthorrhiza and C. zedoaria have been shown to inhibit COX-2 and iNOS activity at concentrations similar to those found for curcumin inhibition (Lee et al., 2002, J. Environ. Pathol. Toxicol. Oncol. 21:141–148). Because curcuminoids are only a small fraction of turmeric, it would be beneficial if other active compounds could be isolated and identifies.